Project Summary/Abstract Post-traumatic Stress Disorder (PTSD) is recognized by the NIMH, the Department of Defense, and the Veterans'Administration as a major medical issue. Recent studies indicate that the incidence of PTSD among Iraq and Afghanistan veterans is 20% and may reach 35%, a rate far higher than in the general population. PTSD is not only an illness that affects military personnel;almost eight million Americans suffer from this disorder and it ranks among the most common psychiatric conditions. Current drug therapies for PTSD rely on repurposed antidepressants that are at best only modestly effective, produce undesirable side effects, and have recognized compliance issues. A new approach to pharmacotherapy is needed for significant improvement in clinical outcomes. Arginine Vasopressin (AVP) 1a receptor antagonists represent a potential new approach for the treatment of PTSD;both clinical and preclinical observations support this view. Elevated levels of AVP associated with significant alterations in HPA axis function represent a recently identified, prominent clinical sign in veterans with PTSD. Alterations in HPA axis function are widely documented in PTSD patients. In a newly developed model of predatory fear conditioning, we have shown using fMRI that rats exposed to a natural predator, a ferret, while experiencing the taste of sucrose exhibit a hyperarousal pattern of brain activity in the limbic cortex and hippocampus in response to the taste of sucrose weeks later. Indeed, the brain activity associated with the memory is far greater than that seen during the initial exposure to the predator. A similar pattern of hyperarousal in fear circuits also is seen in PTSD. Importantly, treatment with a highly selective, orally active V1a receptor antagonist from Azevan Pharmaceuticals blocked the hyperarousal when the traumatic memory was triggered by exposure to the conditioned stimulus, i.e., the taste of sucrose. Collectively, these observations provide a strong basis for the development of vasopressin 1a antagonists as an innovative pharmacotherapy for PTSD. This proposal will use a unique predatory fear conditioning paradigm as a preclinical model to test the feasibility of using novel V1a antagonists as a potential new pharmacotherapy for PTSD. The model will be used to extend preliminary findings that showed that a novel, orally active vasopressin 1a receptor antagonist effectively blocked the hyperarousal pattern of brain activity associated with the traumatic memory triggered by exposure to sucrose. Positive results in the proposed studies will establish the basis for Phase II studies that will provide more in-depth preclinical assessments of the V1a antagonist approach for treating PTSD. . PUBLIC HEALTH RELEVANCE: Project Narrative Post-traumatic Stress Disorder (PTSD) is recognized by the National Institute of Mental Health, the Department of Defense, and the Veterans'Administration as a major medical issue. Current drug therapies for PTSD rely on repurposed antidepressants that are at best only modestly effective, produce undesirable side effects, and have recognized compliance issues. A new approach to pharmacotherapy is needed for significant improvement in clinical outcomes. Arginine Vasopressin (AVP) 1a receptor antagonists represent a potential new approach for the treatment of PTSD based on clinical and preclinical observations. This proposal will use a unique predatory fear conditioning paradigm as a preclinical model to test the feasibility of using novel V1a antagonists as a potential new pharmacotherapy for PTSD.